The peroxisome proliferator-activated receptors (PPARs) are considered to be metabolic sensors regulating the expression of genes involved in glucose and lipid homeostasis. They are members of nuclear receptor superfamily of RXR heterodimers and are ligand-activated transcription factors. Agonists of the PPARα (e.g. Gemfibrozil) and PPARγ (e.g., Avandia®) subtypes are used for the treatment of dyslipidemias and diabetes, respectively. Each receptor has a distinct tissue distribution with PPARα showing highest expression in liver, PPARγ in adipose tissue and PPARδ having the widest distribution being ubiquitously expressed in adult rat (Braissant et al., 1996) and in humans, expression was found in many different tissues involved in lipid metabolism including liver, kidney, abdominal adipose and skeletal muscle (Auboeuf et al., 1997).
Recently, potent ligands for PPARδ have been published allowing a better understanding of its function in lipid metabolism (Barak et al, 2002; Oliver et al., 2001; Tanaka et al, 2003; Wang et al., 2003). The main effect of these compounds in db/db mice (Leibowitz et al., 2000) and obese rhesus monkeys (Oliver et al., 2001) was an increase of high density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides with little effect on glucose (although insulin levels were decreased in monkeys). HDL-C serves to remove cholesterol from peripheral cells through a process called reverse cholesterol transport. The first and rate-limiting step, which is a transfer of cellular cholesterol and phospholipids to the apolipoprotein A-I component of HDL, is mediated by the ATP binding cassette transporter A1 (ABCA1) (Lawn et al., 1999). PPARδ activation appears to increase HDL-C through transcriptional regulation of ABCA1 (Oliver et al., 2001). Therefore, by inducing ABCA1 mRNA in macrophages, PPARδ agonists could increase HDL-C levels in patients and remove excess cholesterol from lipid-laden macrophages, one of the major players in atherosclerotic lesion development. This would be an alternative therapy to the statin drugs, which show little effect on HDL-C and mainly decrease LDL-C or the fibrates, the only marketed PPARα agonists, having low potency and inducing only modest HDL-C elevations. In addition, like the fibrates, PPARδ agonists have the potential to also reduce triglycerides, an additional risk factor for cardiovascular disease.
Examples of known PPAR delta agonists variously useful for hyperlipidemia, diabetes, or atherosclerosis include L-165041 (Leibowitz et al., 2000) and GW501516 (Oliver et al., 2001). There is a continuing need for new PPAR delta agonists. There is a further need for new PPAR delta agonists that increase HDL-C, lower LDL-C, and/or lower cholesterol. There is a further need for new PPAR delta agonists for the treatment of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof.